Arnon I. Dreyfuss

Docetaxel: an active drug for squamous cell carcinoma of the head and neck.

PURPOSE We conducted a phase II study designed to evaluate the activity, safety, and tolerability of docetaxel (Taxotere: Rhône-Poulenc Rorer Pharmaceuticals Inc, Collegeville, PA) in patients with advanced, incurable, or recurrent squamous cell carcinoma of the head and neck (SCCHN) who had not received prior palliative chemotherapy. PATIENTS AND METHODS Thirty-one patients with measurable, locoregional, or metastatic SCCHN were treated with docetaxel, administered at a dose of 100 mg/m2 as a 1-hour intravenous (i.v.) infusion once every 21 days on an outpatient basis. All patients were premedicated with dexamethasone, diphenhydramine, and cimetidine. Prophylactic administration of growth factors or antiemetics was not permitted. RESULTS Thirty-one patients were treated. Twenty-nine patients were assessable for response and 30 for toxicity. Four of 31 patients (13%) achieved complete response (CR), nine (29%) achieved partial response had stable disease (SD) and seven (23%) experienced progression of disease (PD). The major response rate was 42% (95% confidence interval [CI], 24% to 60%). The median duration of responses was 5 months (range, 2 to 14). The principal toxicity was leukopenia, which occurred with rapid onset and brief duration. Sixteen patients (53%) experienced nadir fever, and 13 required dose reduction. Hypersensitivity reactions occurred in four patients. Grade 3 peripheral neuropathy occurred in two patients; grade 2 or 3 fatigue occurred in six (20%) and 10 (33%), respectively. Minimal edema (grade 1) occurred in five patients (17%). Clinically significant mucositis, diarrhea, or dermatitis were not observed. CONCLUSION Docetaxel has major activity against SCCHN. It appears to be well tolerated in this group of patients and can be safely administered on an outpatient basis. Premedication with dexamethasone, cimetidine, and diphenhydramine is associated with a reduced incidence of significant edema, hypersensitivity reactions, and dermatologic toxicities.

Continuous Infusion High-Dose Leucovorin with 5-Fluorouracil and Cisplatin for Untreated Stage IV Carcinoma of the Head and Neck

STUDY OBJECTIVE To study the activity of continuous infusion cisplatin, 5-fluorouracil, and high-dose leucovorin (PFL) as induction chemotherapy in patients with previously untreated, advanced squamous cell carcinoma of the head and neck. DESIGN Nonrandomized, prospective trial. SETTING A comprehensive cancer center. PATIENTS Thirty-five patients (4 patients [11%], stage III; 31 patients [89%], stage IV [MO]), all evaluable for response and toxicity. INTERVENTIONS Two to three cycles of PFL before definitive, local-regional therapy (surgery and radiation therapy or radiation therapy alone). Chemotherapy included continuous intravenous infusion of cisplatin (25 mg/m2 body surface area daily, days 1 through 5); 5-fluorouracil (800 mg/m2 body surface area daily, days 2 through 6); and leucovorin (500 mg/m2 body surface area daily, days 1 through 6) administered once every 28 days. Pathologic response was evaluated by surgical resection or biopsy. Serum-reduced folates were measured before and 18 hours after the initiation of chemotherapy. RESULTS A clinical response to PFL was achieved in 28 of 35 (80%) patients: 23 (66%) patients had a complete response (90% CI, 50% to 79%) and 5 (14%) patients, a partial response. A complete response was confirmed pathologically in 14 of 19 (74%) patients. The most common toxicity was mucositis (grade 2 to 3; 94% of patients). Dose reduction for toxicity was necessary in 11 (31%) patients. There were no treatment-related deaths. Serum levels of leucovorin and (6S)5-methyltetrahydrofolate were measured in 7 patients. After 18 hours, the mean leucovorin level (+/- SD) was 34.3 +/- 1.5 mumol/L, of which only 8.0 +/- 0.5% was the active 6S isomer. The mean serum (6S)5-methyltetrahydrofolate was 9.2 +/- 0.6 mumol/L. CONCLUSIONS Continuous infusion cisplatin, 5-fluorouracil, and high-dose leucovorin is a new and highly active chemotherapy regimen that can achieve clinical and pathologically confirmed complete responses in a substantial proportion of patients with advanced, local-regional squamous cell carcinoma of the head and neck. Further studies are needed to confirm the activity of PFL and to determine its potential impact on local tumor control and disease-free and overall survival.

Induction chemotherapy with docetaxel, cisplatin, fluorouracil, and leucovorin for squamous cell carcinoma of the head and neck: a phase I/II trial.

PURPOSE A phase I/II trial of docetaxel, cisplatin, fluorouracil (5-FU), and leucovorin (TPFL5) induction chemotherapy for patients with locally advanced squamous cell carcinoma of the head and neck (SCCHN). PATIENTS AND METHODS Twenty-three previously untreated patients with stage III or IV SCCHN and Eastern Cooperative Oncology Group functional status less than or equal to 2 were treated with TPFL5. Postchemotherapy home support included intravenous fluids, prophylactic antibiotics, and granulocyte colony-stimulating factor (G-CSF). Docetaxel dose was escalated to determine the maximum-tolerated dose (MTD). Fifteen patients were treated with three cycles of TPFL5 at MTD. Patients who achieved either a partial response (PR) or complete response (CR) to three cycles of TPFL5 then received definitive twice-daily radiation therapy. Toxicity and clinical and pathologic response to TPFL5 were assessed. RESULTS Twenty-three patients received a total of 69 cycles of TPFL5. The MTD was determined to be docetaxel 60 mg/m2. Dose-limiting toxicity (DLT) was neutropenia. Additional significant toxicities at MTD were nausea, mucositis, diarrhea, peripheral neuropathy, and sodium-wasting nephropathy. The overall response rate to TPFL5 was 100%, which included 14 of 23 (61%) clinical CRs and nine of 23 (39%) clinical PRs. Primary-site clinical and pathologic CR rates were 19 of 22 (86%) CRs and 20 of 22 (91%) CRs, respectively. Eight patients had less than a CR in the neck to chemotherapy and, therefore, had postradiation neck dissections, four of which were positive for residual tumor. CONCLUSION TPFL5 is a tolerable induction regimen in patients with good performance status. The DLT is neutropenia with significant mucositis, diarrhea, peripheral neuropathy, and sodium-wasting nephropathy. The high response rates to TPFL5 justify further evaluation of this combination of agents in the context of formal clinical trials.

Cyclophosphamide, doxorubicin, and cisplatin combination chemotherapy for advanced carcinomas of salivary gland origin

Thirteen patients with carcinomas of major and minor salivary gland origin (nine adenoid cystic carcinomas and four adenocarcinomas) were treated with cyclophosphamide (500 mg/m2), doxorubicin (50 mg/m2), and cisplatin (50 mg/m2) (CAP) by intravenous injections on the first day of a 28‐day regimen. Sixty‐one cycles of CAP were administered (mean, 4.7 cycles per patient). Eleven patients were treated for palliation of recurrent disease (locoregional, ten; lung, ten; liver, three; and bone, three). Two patients untreated previously, one with extensive local disease involving the base of the skull and one with a solitary lung metastasis (resected with a positive margin) and an initially unappreciated base of tongue primary, received two cycles of CAP followed by local treatment and adjuvant CAP. Previous therapy for the 11 patients with recurrent disease included surgery (ten), radiotherapy [RT(11)], chemotherapy (three), or hormonal therapy (two). Three complete and three partial responses to chemotherapy were noted for an overall response rate of 46%. The median duration of response in palliative patients was 5 months (range, 2 to 9). Of the two patients receiving induction CAP, one relapsed with distant disease 26 months after treatment, and the other remains disease‐free after 60 months of follow‐up examination. Chemotherapy was well tolerated generally, and no chemotherapy‐related deaths occurred. One hypertensive patient suffered a stroke after 3 cycles of therapy. CAP is an active regimen against salivary gland carcinomas and deserves further study. Also, it may be of value as induction or adjuvant treatment for patients with advanced disease untreated previously.

Induction chemotherapy with cisplatin, fluorouracil, and high-dose leucovorin for squamous cell carcinoma of the head and neck: long-term results.

PURPOSE A phase II trial of cisplatin, fluorouracil, and leucovorin (PFL) induction chemotherapy in patients with locally advanced squamous cell carcinomas of the head and neck region (HNCA). PATIENTS AND METHODS One hundred two patients (stage III/IV, previously untreated) were treated with induction PFL. Patients with resectable primary tumor site lesions and clinical complete response (CR) were offered radiotherapy (RT) without surgery to the primary tumor site. Response, toxicity, local-regional therapy, survival, and preservation of the primary tumor site were assessed. RESULTS Among 279 courses, the overall response rate was 81%. Nineteen (19%) failed to respond, including three who died during therapy. Sixty-seven (69%) of 97 with assessable primary lesions had a clinical CR at the primary tumor site. Pathologic CR was recorded in 46 of 55 (84%) clinical CR patients who had biopsies performed on the primary tumor site. Toxicities resulted in unexpected hospitalizations in 19% of cases. After definitive local-regional therapy, 84 (82%) were disease-free including 71 (69%) with preserved primary tumor site anatomy. With a median follow-up time of 63 months, the cause-specific, overall (OS), and failure-free survival (FFS) rates at 5 years are 58%, 52%, and 51%. Local failure occurred in 29 of 102 (29%) and the local control rate at 5 years was 68%. CONCLUSION PFL has significant activity with acceptable toxicity in patients with advanced disease who have a good performance status. Preservation of the primary tumor site could be achieved without apparent loss of local control or survival. Management of neck disease by surgery or RT must be individualized and separate from management of primary tumor. Survival compares favorably with similar trials of induction chemotherapy or chemoradiotherapy.

Nasopharyngeal Carcinoma: The Dana-Farber Cancer Institute Experience with 24 Patients Treated with Induction Chemotherapy and Radiotherapy:

Nasopharyngeal carcinoma traditionally has been treated with radiotherapy alone. Although the probability of cure for patients with stage I and II nasopharyngeal carcinoma is high, the probability of cure for patients with stage III and IV disease is poor because of a higher rate of local-regional and distant failure. Between February 1981 and August 1986, 24 patients with previously untreated, stage IV nasopharyngeal carcinoma were treated with two to four monthly courses of cisplatin-based combination chemotherapy prior to radiotherapy. A response to induction chemotherapy was recorded in 75% of patients (29% complete response and 46% partial) prior to radiotherapy. By actuarial estimate with a median follow-up of 42 months, the 2-year failure-free survival for all patients was 57%. In conclusion, induction chemotherapy has significant activity in nasopharyngeal carcinoma. The toxicity of this approach, as well as the influence of initial histopathology and response to chemotherapy on survival, will be discussed.

Reduced membrane protein associated with resistance of human squamous carcinoma cells to methotrexate and cis-platinum

A membrane protein recognized by monoclonal antibody SQM1 was identified in human squamous carcinomas, including those originating in the head and neck (SqCHN), lung and cervix. Cell lines derived from SqCHN of previously untreated patients expressed high amounts of this protein. In contrast, many cell lines established from SqCHN of patients previously treated with chemotherapy and/or radiation showed diminished amounts of this SQM1 protein. The expression of SQM1 antigen was determined in several SgCHN cell lines made resistant by exposure to methotrexate (MTX) in vitro. The parent cell lines all exhibited strong binding to SQM1 antibody. The MTX-resistant sublines showed much lower membrane binding of SQM1. The lowest SQM1 reactivity was found in cell lines with high resistance to MTX and with diminished rate of MTX transport. Some highly MTX-resistant cell lines which had high levels of dihydrofolate reductase, but which retained a high rate of MTX transport, also retained high levels of SQM1 binding. Reduced SQM1 protein was also found in SgCHN cells which developed resistance to the alkylating drug cis-platinum (CDDP) and which showed reduced membrane transport of CDDP. Cell growth kinetics and non-specific antigenic shifts were not responsible for the differences in SQM1 binding between the parent cell lines and their drug-resistant sublines. The finding of a novel protein which is reduced in cells resistant to MTX and CDDP could contribute to our understanding of the basic mechanisms of drug resistance. By detecting SQM1 protein in clinical specimens, it may be possible to monitor the development of drug resistance in tumors.

Neo-adjuvant infusion Cisplatin, 5-FU and high-dose leucovorin for squamous cell carcinoma of the head and neck (SCCHN): high rates of complete response (CR) and definitive radiotherapy as primary site management

The role of Neo-Adjuvant chemotherapy for patients with advanced SCCHN remains controversial. While results from randomized trials of Neo-Adjuvant therapy have confirmed an association between response and treatment outcome, an improvement in survival has not been reported. Critical review of latter studies however, reveals flaws which limit the value of their findings [1]. An improvement in the survival of patients who receive Neo-Adjuvant therapy for SCCHN may not be confirmed until the rate of CR is consistently over 50 % and local-regional treatment is optimal [1].

Regional control after induction chemotherapy for adbanced squamous cell carcinoma of the head and neck: A retrospective analysis of 303 patients

Induction chemotherapy for squamous cell carcinomas of the head and neck has been the subject of a number of clinical trials with ambiguous results. Response data from phase II studies suggest a 20–40% complete response rate which has lead to an association between chemotherapy and survival and an improvement in survival when compared to historical controls. Eight separate prospective randomized trials have been published to date. Although these have yet to show an improvement in survival, there are critical flaws in each, which limit their interpretation and leave the role of induction chemotherapy an open question [1].